Research Article Details
| Article ID: | A24306 |
| PMID: | 23022226 |
| Source: | Biochem Pharmacol |
| Title: | High-carbohydrate diets induce hepatic insulin resistance to protect the liver from substrate overload. |
| Abstract: | In population studies hepatic steatosis in subjects with Non-alcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance. This association has encouraged debate whether hepatic steatosis is the cause or the consequence of hepatic insulin resistance? Although genome-wide studies have identified several gene variants associated with either hepatic steatosis or type 2 diabetes, no variants have been identified associated with both hepatic steatosis and insulin resistance. Here, the hypothesis is proposed that high-carbohydrate diets contribute to the association between hepatic steatosis and insulin resistance through activation of the transcription factor ChREBP (Carbohydrate response element binding protein). Postprandial hyperglycaemia raises the hepatic concentrations of phosphorylated intermediates causing activation of ChREBP and induction of its target genes. These include not only enzymes of glycolysis and lipogenesis that predispose to hepatic steatosis but also glucose 6-phosphatase (G6PC) that catalyses the final reaction in glucose production and GCKR, the inhibitor of hepatic glucokinase that curtails hepatic glucose uptake. Induction of G6PC and GCKR manifests as hepatic glucose intolerance or insulin resistance. Induction of these two genes by high glucose serves to safeguard intrahepatic homeostasis of phosphorylated intermediates. The importance of GCKR in this protective mechanism is supported by "less-active" GCKR variants in association not only with hepatic steatosis and hyperuricaemia but also with lower fasting plasma glucose and decreased insulin resistance. This supports a role for GCKR in restricting hepatic glucose phosphorylation to maintain intrahepatic homeostasis. Pharmacological targeting of the glucokinase-GCKR interaction can favour either glucose clearance by the liver or intrahepatic metabolite homeostasis. |
| DOI: | 10.1016/j.bcp.2012.09.019 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D545 | Pig placenta extract | Biological extract | -- | -- | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |